lung cancer (NSCLC) who do not harbor an actionable driver oncogene depends upon PD-L1 expression level and histology, according to Gregory J. Riely, MD, PhD."/>
lung cancer (NSCLC) who do not harbor an actionable driver oncogene depends upon PD-L1 expression level and histology, according to Gregory J. Riely, MD, PhD."/>

The rapid pace, he added, of clinical trial findings during the past 7 months have prompted the evolution in first-line options. “It’s transformed how we treat patients with initial therapy,” said Riely, a medical oncologist who is vice chair of Clinical Research in the Department of Medicine at Memorial Sloan Kettering Cancer Center.

To update clinicians on the new landscape in NSCLC, Reily conducted a presentation at the 2018 New York Lung Cancers Symposium, where he explained that patients with PD-L1 expression ≥50% would be candidates for single-agent immunotherapy with pembrolizumab (Keytruda) while those whose status is below that level would be considered for combination PD-1/PD-L1–targeting immunotherapy and chemotherapy. The choice of the combination would then depend upon histology.

Before delving into the details of treatment options, Riely emphasized that the matter of establishing whether a patient has a driver oncogene also is becoming more multifaceted. He said the standard of care requires testing for mutations in EGFR and BRAF and fusions in ALK and ROS1 genes. However, Riely noted that therapies targeting RET, MET exon 17, NTRK, and HER2 alterations also are in development, demonstrating the value of conducting more extensive testing.

In all, 4 immune checkpoint inhibitors are FDA approved for treating patients with NSCLC: the PD-1 inhibitors pembrolizumab and nivolumab (Opdivo) and the PD-L1 inhibitors atezolizumab (Tecentriq) and durvaulamb (Imfinzi). Pembrolizumab is approved in frontline settings as monotherapy for patients with metastatic NSCLC with PD-L1 expression ≥50% and in combination with chemotherapy regimens. Nivolumab and atezolizumab are indicated for patients who have progressed during or following platinum-containing chemotherapy, while durvalumab is approved for unresectable stage III disease that has not progressed after chemoradiotherapy.

Moreover, participants treated with pembrolizumab experienced fewer treatment-related adverse events (AEs) of any grade than did those who received chemotherapy (73.4% vs 90.0%, respectively) and fewer AEs grade ≥3 (26.6% vs 53.3%).1 However, Riely noted that pembrolizumab is associated with immune-related AEs and that patients should be monitored for these effects, particularly those affecting thyroid function.

The findings made “it clear that this was the new standard of care for patients with ≥50% PD-L1” expression, so the next question became whether this would be the case for those whose status was below that threshold.

In the phase III KEYNOTE-042 study, pembrolizumab monotherapy was tested against the chemotherapy doublet of carboplatin plus paclitaxel or pemetrexed (Alimta) in 1274 patients with previously untreated locally advanced or metastatic NSCLC of any histology with a tumor proportion score (TPS) ≥1%. TPS is defined as the percentage of tumor cells with membranous PD-L1 staining.2

The findings confirm the benefit of pembrolizumab therapy for patients with TPS ≥50%, according to results presented at the 2018 ASCO Annual Meeting.2 The median OS for this group was 20 months (95% CI, 15.5-24.9) with pembrolizumab compared with 12.2 months (95% CI, 10.4-14.2) with the combination of carboplatin and either paclitaxel or pemetrexed (HR, 0.69; 95% CI, 0.56-0.85; P = .0003).

“There’s no clear benefit for pembrolizumab over chemotherapy in this context,” Riely said, of the 1% to 49% group. “The hazard ratio is nearly 1 and the confidence intervals overlap. This tells us that it’s probably not reasonable to move the bar down from 50% to 1% but we can think about that when we see our patients.”

Histology-Based Decisions

Nonsquamous NSCLC

When choosing combination immunotherapy and chemotherapy, the decision about which option hinges on histology, Riely said.

For patients with nonsquamous disease, there are 2 regimens with recently reported results: (1) pembrolizumab plus carboplatin and pemetrexed, and (2) atezolizumab with bevacizumab (Avastin), carboplatin, and paclitaxel (ABCP).

In the phase III KEYNOTE-189 trial, the pembrolizumab combination demonstrated an improvement in OS compared with chemotherapy alone regardless of PD-L1 expression status. The 12-month OS rate was 69.2% (95% CI, 64.1-73.8) with the pembrolizumab regimen compared with 49.4% (95% CI, 42.1-56.2) for those who received chemotherapy (HR for death, 0.49; 95% CI, 0.38-0.64; P <.001). Among participants with a TPS <1%, the 12-month OS rate was 61.7% with the pembrolizumab regimen versus 52.5% with chemotherapy alone, which translated into an HR for death of 0.59 (95% CI, 0.38-092).3